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==TRYPANOSOMA BRUCEI TRYPANOTHIONE REDUCTASE IN COMPLEX WITH 3,4-DIHYDROQUINAZOLINE INHIBITOR (DDD00065414)== | |||
<StructureSection load='2wp5' size='340' side='right' caption='[[2wp5]], [[Resolution|resolution]] 2.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2wp5]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_brucei Trypanosoma brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WP5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WP5 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=MRD:(4R)-2-METHYLPENTANE-2,4-DIOL'>MRD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=WP5:METHYL+[(4S)-6-BROMO-2-METHYL-4-PHENYLQUINAZOLIN-3(4H)-YL]ACETATE'>WP5</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2wov|2wov]], [[2woi|2woi]], [[2wow|2wow]], [[2wp6|2wp6]], [[2wpe|2wpe]], [[2wpf|2wpf]], [[2wpc|2wpc]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Trypanothione-disulfide_reductase Trypanothione-disulfide reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.8.1.12 1.8.1.12] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wp5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wp5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wp5 RCSB], [http://www.ebi.ac.uk/pdbsum/2wp5 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Trypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay. | |||
Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography.,Patterson S, Alphey MS, Jones DC, Shanks EJ, Street IP, Frearson JA, Wyatt PG, Gilbert IH, Fairlamb AH J Med Chem. 2011 Oct 13;54(19):6514-30. Epub 2011 Sep 1. PMID:21851087<ref>PMID:21851087</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Trypanothione reductase|Trypanothione reductase]] | *[[Trypanothione reductase|Trypanothione reductase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Trypanosoma brucei]] | [[Category: Trypanosoma brucei]] | ||
[[Category: Trypanothione-disulfide reductase]] | [[Category: Trypanothione-disulfide reductase]] | ||
[[Category: Alphey, M S | [[Category: Alphey, M S]] | ||
[[Category: Fairlamb, A H | [[Category: Fairlamb, A H]] | ||
[[Category: Patterson, S | [[Category: Patterson, S]] | ||
[[Category: Flavoprotein]] | [[Category: Flavoprotein]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
Revision as of 16:53, 17 December 2014
TRYPANOSOMA BRUCEI TRYPANOTHIONE REDUCTASE IN COMPLEX WITH 3,4-DIHYDROQUINAZOLINE INHIBITOR (DDD00065414)TRYPANOSOMA BRUCEI TRYPANOTHIONE REDUCTASE IN COMPLEX WITH 3,4-DIHYDROQUINAZOLINE INHIBITOR (DDD00065414)
Structural highlights
Publication Abstract from PubMedTrypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay. Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography.,Patterson S, Alphey MS, Jones DC, Shanks EJ, Street IP, Frearson JA, Wyatt PG, Gilbert IH, Fairlamb AH J Med Chem. 2011 Oct 13;54(19):6514-30. Epub 2011 Sep 1. PMID:21851087[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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